1&#39;, 1&#39;-dihalo and 1&#39;-carboxy-cyclopropanoandrostene derivatives



- iiiiS 3,089,387 ,1-D.IHALO AND 1'=CARBOXY-YCLOPRUPANO- ANDRGSTENE DERIVATIVES Lawrence H. Knox, Mexico City, Mexico, assignor to Syntex S.A., Mexico City, Mexico, a corporation of Mexico No Brawing. Filed Apr. 13, 1962, Ser. No. 187,223

29 flaims. (Cl. zen-3am The present invention relates to novel cyclopentanophenanthrene derivatives and to a process for the production thereof.

More specifically the present invention relates to novel In the above formulas X represents hydrogen, fluorine or chlorine; R represents hydrogen or methyl; R may be hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R indicates hydrogen, lower alkynyl or lower alkyl; R represents hydrogen or lower alkyl.

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopeutylpropionate, aminoacetate and B-chloropropionate.

The compounds represented by the above formulas are agents with a favorable anabolic-androgenic ratio, exhibit 338,387 Patented Mar. 5, 1963 ice anti-ovulatory and anti-estrogenic properties and inhibit the pituitary gland.

The novel compounds of the present invention are prepared in accordance with the following equation:

R Ii

OBI-00 0R 11-0 In the above formulas X, R, R and R have the same meaning as previously defined; Ac represents an acyl group, preferably the acetyl group.

The starting compound (I) of the above outlined process is prepared from the corresponding testosterone derivative by sodium borohydride or lithium aluminum hydride reduction, followed by reflux of the produced S-hydroxylM-derivative with 50% acetic acid and conventional acylation of the obtained A -androstadien-17B- 01. The said starting compound is selected from the group consisting of the 17-acylates of A -androstadien- 17,8 ol, l7a-lower '.alkyl-A -androstadien-17 5-01, l7e: lower a1kynyl-A -androstadien-l7 8-01 and the 19-nor derivatives thereof.

In accordance with the above equation, the starting compound (I) is treated with an alkali metal trichloroacetate, preferably the sodium salt, in a suitable solvent such as bis-(2-methoxyethyl)-ether at approximately C. for a period of time of the order of 1.5 hours and the product thus obtained is chromatographed, for example on Florisil, thus affording the corresponding 1',1'-dichlorocyclopropano-(2',3';3a,4a) A androsten- 1718-01 (H; X CI) and l,l-dichlorocyclopropano-(2',3'; 55,6 3)-A5-androsten-17fl-ol (III; X=Cl) derivatives.

Upon treatment of the starting compound (I) with diazomethane in the presence of copper powder followed by chromatography of the resulting product, there are obtained the corresponding cyclopropauo-(1',2';3e,4a)-

3 A -androsten-17B-ol- (II; X H) and cyclopropano-(l, 2;5/8,6 S')-A -androsten-17B-ol (III; X=H) derivatives.

Upon reaction of the starting compound (I) with an alkali metal monochloro difluoro acetate, preferably sodium monochloro difiuoro acetate, in a suitable solvent such as diglyme at reflux temperature, for a period of time of the order of 20 minutes, followed by chromatography of the resulting product, there are produced the corresponding 1',1-difiuorocyclopropano (2',3';3cc,4a)- A -androsten-17 8-ol (II; X=F) and 1',l-difluorocyclopropano-(2',315,9,6B)-A -androsten-17[3-ol (III; X=F) derivatives.

The reaction of the starting compound (I) with a lower alkyl diazoacetate such as ethyl diazoacetate, in the presence of copper powder, in a suitable solvent such as 1,2-dimethoxy-ethane, at reflux temperature and for a period of time of the order of four and a half hours, yields a product which upon chromatography is separated into the corresponding 1'-carbethoxycyclopropano-(2,3; 20,4a)-A -androsten-17;3-ol (IV; R =ethyl) and 1'-carbethoxycyclopropano (233255365)-A -androsten-l7 3-ol- (V; R =ethyl) derivatives.

The compounds obtained hereinabove (II, III, IV, V) wherein R is an acyl group i.e. the 17fi-acyloxy derivatives, are conventionally saponified with a base to the corresponding 17/3-free alcohols (II, III, IV, V; R =H) which in turn are conventionally acylated to the corresponding 17,8-acylates, wherein the acyl group may be dilferent from the previously hydrolyzed group.

In the case of the compounds represented by formulas IV and V wherein R is a lower alkyl, the saponification with a base also hydrolyzes the said lower alkyl group, thus afiording the corresponding 1-carboxycyclopropano- (2',3;3a,4u)-A -androsten-17fi-ol (IV; R =H) and 1'- carboxycyclopropano (2',3;5fl,6,8) A androsten 1718- 01 (V; R =H) derivatives.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

PREPARATION l A solution of 1 g. of testosterone in 50 cc. of tetrahydrofuran was added over a 30 minutes period to a stirred suspension of 1 g. of lithium aluminum hydride in 50 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered off and thoroughly washed with hot ethyl acetate, the combined organic solutions upon evaporation yielded a crude material, which was purified by crystallization from acetone-hexane thus giving A -androstene-3B,l7 3rdiol.

1 g. of the latter product was heated on the steam bath with 100 cc. of 50% acetic acid under nitrogen for 1 hour, it was then poured into water. The precipitate was, collected, washed Well with water, dried and recrystallized from acetone-hexane, thus furnishing A -andro stadien-17B-ol.

By the above procedures, 19-n-or-testosterone, 17ozethyl-testosterone, 17a-methyl-19-nor-testosterone, 17w ethinyl-testosterone and 17a-ethinyl-19-nortestosterone were respectively converted into 19-nor-A -androstadien- 175-01, 17methyl-A -andros-tadien-17;3-ol, Not-methyl- 19-nor-A -androstadien-l7 8-01, 17u-ethinyl-a -androstadien-175-ol and 17a-ethinyl-19-nor-A -androstadien-175-. ol.

PREPARATION 2 A mixture of l g. of A -androstadien-17mol, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured, into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave the acetate of A 5-androstadien-17 8-01.

By the same procedure there was treated l9'-nor-A -5- androstadien-flflcl to produce the acetate of 1*9-nor-A androstadien-UB-ol.

PREPARATION 3 To a solution of 5 g. of 17a-ethyl-A -androstadien- 17 3-01 in cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. of acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the excess 'anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from etherhexane produced the acetate of 17u-ethyl-A -androstadien-l7fl-ol.

"Using exactly the same conditions, 17x-methyl-19-nor- A -androstadien-17B-ol, 17a-ethinyl-I9EnOr-A eandrostadien-1713-ol and 17a-ethinyl-A -androstadien-175-01 were transformed into the corresponding acetates.

Example I To a solution of 2 g. of the acetate of A -androstadien-Ufl-ol in 50 cc. of diglyme ('bis(2-methoxyethyl )ether) at C. there were added 4.4 g. of sodium trichloroacetate in 10 equal portions at 10 minutes intervals. The reaction mixture was then cooled, the formed sodium chloride filtered oh and the filtrate evaporated to dryness under reduced pressure. The residue was conventionally chromatographed on Florisil, thus yielding two products, which upon crystallization from methanol furnished 1',l-dichlor0cyclopropano- (2',3';3oc,4a) A -androsten 1718 o1 acetate and 1',1'-

dichlorocy-clopropano-(2',3';5[3,6fi) A androsten 17(3- ol-acetate.

Example 11 The acetate of l-9-nor-A -androstadien--01 was treated by the procedure described in Example I, to produce 1',1-dichlorocyclopropano-(2,3';3o:,4u)-l9-nor-A :androsten-17fl-olracetate and 1,1'-dichlorocyclopropano- (21315 536 3)-19rnor-A -androsten-17,8-ol-acetate.

Example 111 The acetate of 17u-ethyl-A -androstadien-17/:3Fol was treated in accordance with Example I, thus furnishing l,l dichloro-cyclopropano (2',3';3zx,4u) 17a ethy A -androsten-17,8-ol-acetate and 1,1-dichlorocyclopropano-(2',3;5fi,6fi)-17a-ethyl-M-androsten-l7fi-0l-acetate.

Example IV The acetate of 17a-methyl-19-nor-A -androstadien- 175-01 was treated according to Example I, thus giving 1',1'-dichlorocycloprop-ano (2,3;3x,4u.)-17a-methy1-19- nor-A -androsten-l7 3-ol-acetate and l,l'-dichlorocyclopropano-(2',3;5fi,6 3) 17a methyl-19-nor-A -androsten- 17 3-ol-aicetate.

Example V Example VI The acetate of 19-nor-A Pandmstadien-17,8-01 was treated following the procedure described in Example V, to produce cyclopropano-(1,2;3a,4. x)-1'9Fnor-A -andros Example VII The acetate of 17a-ethyl-A -audrostadien-175-01 was treated in accordance with Example V, thus furnishing QYClOpIOPElIi'O-(l1',2';3o:,4u) l7a ethyl-d androsten-l7fi ol-acetate and cyclopropano-(l',2; 5,8,6fi)-l7e-ethyl-A and-rosten-17,8-ol-acetate.

Example VH1 The acetate of l7a-rnethyl-19-nor-A androstadien- 17B-ol was treated according to Example V, thus giving cyclopropano-(1,2';3e,4e) -17a-methyl-19-nor-A androsten-lTfl-ol-acetate and cyclopropano-(l,2';5,6,6t3)- flat-methyl-19-nor-A -androsten-Heel-acetate.

Example IX A mixture of 2 g. of the acetate of A -androstadien- 175-01, 100 cc. of diglyrne and 4 g. of sodium monochloro difiuoro acetate was refluxed for minutes, then cooled to 50 C., an additional 4 g. of the same salt were thereafter added and the resulting mixture again refluxed for 10 minute The reaction mixture was cooled, the formed sodium chloride filtered oil and the filtrate evaporated to dryness under reduced pressure. The residue was conventionally chromatographed on Florisil, thus yielding two products, which upon crystallization from methanol furnished l,1-difluorocyclopropano-(2',323e, 4e)-A. -androsten-l7B-ol-acetate and 1',l-ditiuoro-cyclopropane-(232555;?)-A -androsten-l7fi-ol-acetate.

Example X The acetate of 19-nor-A -androstadien-17fi-ol was treated following the procedure described in Example IX, to produce 1,l-diiiuorocyclopropano-(Z,3';3u,4a)- l9-nor-A -androsten-l7fl-ol-acetate and l,1-ditluorocyclopropano-(2',3;5fi,6fl) l9 nor A androsten-17 3-olacetate.

Example XI The acetate of 17a-ethyl-A -androstadien-1718-01 was treated in accordance with Example IX, thus furnishing: 1',1-difiuorocyolopropano-(2',3';3 x,4et)-l7uethyl A androsten-flfi-ol-acetate and 1',l'-ditluorocyclopropano- (2,3';5,5,6fi)-17a-ethyl-A -androsten-175-ol-acetate.

Example XII The acetate of 17a-rnetl1yl-19-nor-A -androstadien- 17/3-01 was treated according to Example IX, thus giving l',1-difluorocyclopropano (2,3';3a,4ot) 17a-rnethyl-19- nor-M-androsten-175-ol-acetate and 1,1'-difiuoro-cyclo propano-(2',3';5fi,=6fi)-17e-metl1y1-l9-nor-A androsten- Wool-acetate.-

Example XIII A mixture of 2 g. of the acetate of A -androstadien- 175-01 ,20 cc. of 1,2-dirnethoxy-ethane and 300 mg. of freshly prepared copper powder was heated to reflux temperature, then there was added dropwise with stirring, a solution of 3.4 g. of ethyl diazoaceta-te in 5 cc. of 1,2 dirnethoxy-ethane over a period of 2 hours. Refiuxing was continued for an additional 2.5 hours. The catalyst was thereafter filtered off and the filtrate evaporated to dryness. The residue was conventionally chromatographed on Florisil, thus yielding two products which upon crystallization from acetone-hexane furnished 1- caIbethoxy-cyclopropano(2,3;3a,4m)-A androsten-17/3 ol-acetate and 1-caroethoxy-cyclopropano-(2',3;5i3,6fi)- A -androsten-175-ol-acetate.

Example XIV The acetate of 19-nor-A -androstadien-17fi-ol was eated following the procedure described in Example XIII, to produce 1-carbethoxy-cyclopropano-(2',3;3a, 4:1)-19-nor-A -androsten-17/3-ol-acetate and l carbethoxy- U cyclopropano-(Z,3';5p,6,B) 19 nor-A -androsten-17fi-o1- acetate.

Example X V The acetate of 17a-ethyl-A -androstadien-lM-ol was treated in accordance with Example Xill, thus furnishing 1 carbethoxy-cyclopropano-(2,3;3 C,40t)-17!X-6lhyl- M-androstend7B-ol-acetate and 1'-carbethoxy-cyclopropano-(2',3';5 8, 6 3)-17u-ethyl-A -androsten17B-ol-acetate.

Example XVI The acetate of l7a-methyl-l9-nor-A -androstadien- 17fl-ol was treated according to Example XIII, thus giv ing 1'-carbethoxy-cyclopropano-(.2,3';3a,4a)-17a-methyl- 19-nor-A -androsten 17,8 --ol-acetate and l'-carbethoxycyclopropano (2,3';5fi,6,8) 17a methyLIQ-nor-M-androsten-17/3-ol-acetate.

Example XVII sponding products set forth under H.

Example XVIII A mixture of 1 g. of 1',1'-dichloro-cyclopropano- (2',3';3a,4a)-A -androsten-17B-ol 4 cc. of pyridine and 2 cc. of caproic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave l',l-dich1orocy-clopropano-(2',3;3tx,4a)-A -androsten-17p-ol-caproate.

By the same procedure, 1',1'-dichloro-cyclopropano (2,3;3a,4tx)-19-nor-A -androsten-l75-01 and l,1'-difiuoro-cyclopropano (2',3';5p,6e) 19 nor A androsten- 1-75-01 were converted into the respective caproates.

Example XIX To a solution of 5 g. of 1',1'-dichloro-cyclopropano- (2',3';3a,4a)-l7ct-ethyl-A -androsten-l75-01 in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and cc. of propionic anhydride and the mixture was allowed to stand for 24 hours at room tempera- H Example XX The acetate of 17ot-ethinyl-19-nor-A -androstadien-17 8- 01 was, treated by the procedure described in Example I, to produce: 1,l diClllOl'Q-CYClOPI'OPalto-(1,3 5oc,4ot)-170tethinyl- 19-nor-A -androsten-17fi-ol-acetate and 1',1' -dichloro cyclopropano (2,3;5fi,6;8) 17a ethinyl 19- nor-A androsten-17fi-ol-acetate.

Example XXI The acetate of 17aethinyl-l9-nor-A -androstadien-17/3- 01 was treated in accordance with Example V, thus furnishing: cyclopropanol-(1',2;3a,4a)-17a-ethinyl-19-n0r- A -androsten-17p-ol-acetate and cyclopropano-(1,2;5/8, 6p)-17ot-ethinyl19-nor-A -androsten-17B-ol-acetate.

Example XXII The acetate of Hot-ethinyl-l9-nor-A -androstadien-17fi 01 was treated according to Example IX thus giving: 1,1'- difluoro cyclopropano (2,-3;3a,4a)- 17a ethinyl l9- nor-A -androsten-17,8-ol-acetate and l',1 -difluoro-cyclopropane (2,3';5 8,6B) 17a ethinyl 19 nor A androsten-17B-ol-acetate.

Example XXIII The acetate of l7a-ethinyl-l9-nor-A -androstadien-175- 01 was treated following the procedure described in Example XIII, to give: 1-carbethoxy-cyclopropano-(2',3';3a, 4a)-17a-ethinyl-19-nor-A -androsten-17p-ol-acetate and 1'- carhethoxy cyclopropano (2,3;5,6,6p) 17a ethinyll9-nor-A -androsten-l7fl-ol-acetate.

Example XXIV The acetate of 17a-ethinyl-A -androstadien-17 3-01 was treated by the procedure described in Example I, to produce: 1,1 dichloro cyclopropano (2',3';3a,4a)-170tethinyl-M-androsten-l7p-ol-acetate and 1,1-dichlorocyclopropanol (2,3';5,8,6 3) 17a ethinyl-M-androsten- 17fl-ol-acetate.

3 Example XXV The acetate of 17a-ethinyl-A -androstadien-17,9Fo1 was;

treated in accordance with Example V, thus furnishing: cyclopropano (1',2';3oz,40t) 17a ethinyl A androethinyl-A androstcn-17B-ol-acetate.

Example XXVI The acetate of 17aethinyl-A -androstadien-17 8-01 was treated according to Example IX thus giving 1',l'-difluorocyclopropano (2',3;3a,4a) 17c: ethinyl A androsten-17/3-ol-acetate and 1,1-difiuoro-cyclopropano-(2,3'; 55,6,8)-17ot-ethinyl-A -androsten-17,8-ol-acetate.

Example XX VII The acetate of l7aethinyl-A -androstadien-l75-01 was treated following the procedure described in Example XIII, to give: l'-carbeth0xy-cyclopropano-(2',3;3a,4a)- 17a-ethinyl-A -androsten-17/9-ol-acetate and 1-carbethoxcyclopropano (2',3';5p,6e) 17m ethinyl A andro sten-17p-ol-acetate.

Example XX VIII The final compounds of Examples XX, XXI, XXII, XXIV, XXV and XXVI were treated in accordance with Example XVII, thus yielding the corresponding 17,8-freealcohols.

Example XXIX Ego wherein R is selected from the, group consisting ofhydrogen and methyl; R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a lower alkyl group and av lower alkynyl group; and X is selected from the group consisting of hydrogen, fluorine and chlorine.

2. 1,1' dichlorocyclopropano (2',3';3ot,4a) A aud'rosten-17fl-ol.

3. 1',1 difluorocyclopropano (2',3';3ot,4a) A androsten-l7 13-01.

5. Cyclopropano (1',2';3a,4a) 19 nor A androsten-17fi-ol.

6. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a lower alkyl group and a lower alkynyl group; and X is selected from the group consisting of hydrogen, fluorine and chlorine.

7. 1,1' dichlorocyclopropano (2',3';55,6B) A androsten-17B-ol.

8. 1,1' difluorocyclopropano (2',3';5,6,6 8) A androsten-17B-ol.

9. Cyclopropano-(l',2';5 3,6fl)-A -androsten-l718-01.

10. Cyclopropano (13235555) 19 nor A -androsten-17B-ol.

11. A compound of the following formula:

binooom wherein R is selected from the group consisting of hydrogen and methyl; R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a lower alkyl group and a lower alkynyl group; and R is selected from the group consist ing of hydrogen and a lower alkyl group.

12. The acetate of 1'-carbethoxycyclopropano-(2,3'; 304,400-A -androsten-17B-ol.

13. The acetate of 1'-carbethoxycyclopropano-(Z',3; 3a,4u)-19-nor-A -androsten--01.

14. 1' carboxycyclopropano (2',3';3a,4oc) A androsten- 17,8-01.

15. 1' carboxycyclopropano (2',3';30c,4a) 19 nor- A -androsten-l7/3-ol.

16. A compound of the following formula:

011-- C 0 0 R wherein R is selected from the group consisting of hydro gen and methyl; R is a member of the group consisting of No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 